PROJECT ABSTRACT Project 3: Human Long-lived Plasma Cell Survival and the Role of the BM Microniche. Long-lived plasma cells (LLPC) sustain protective antibody production for a lifetime and require the bone marrow microniche to sustain survival. In our lab, we have definitively linked the long-lived viral serum antibody source to the LLPC cellular compartment within the human bone marrow (BM) (CD19-CD38hiCD138+) and developed in vitro BM microniche cultures that mimics the BM microenvironment to sustain PC survival. In this application, we will study the role of the BM microniche on LLPC generation and maintenance by (1) understanding the transcriptional and epigenetic regulation of BM LLPC, (2) understanding the LLPC fate determinants especially the BM adaptation to a hypoxic BM microenvironment and (3) elucidating the essential LLPC survival factors provided by the BM microniche. The significance of this work will be to understand the role of the BM microniche in LLPC survival for life-long antibody protection.